In both humans and laboratory animal models, exposure to alcohol during development has been shown to cause a multitude of dose-dependent effects on the structure and function of the central nervous system, resulting in a range of physical, behavioral, cognitive and social dysfunctions that are collectively termed fetal alcohol spectrum disorders (FASD). The N-methyl-D-aspartate (NMDA) receptor (NMDAR) has been shown to play a critical role in learning and memory, and consequently has been a focus of studies aiming to identify mechanisms that underlie the detrimental effects of prenatal alcohol exposure (PAE) on cognition. The proposed studies aim to test the hypothesis that PAE alters the distribution of NMDAR subunits between synaptic and extrasynaptic compartments (Aim 1) and/or the properties of the NMDAR-channel complex (Aim 2) leading to impaired NMDAR function in the mouse dentate gyrus. Two specific aims have been developed to test this hypothesis: Aim 1: PAE alters the distribution of NMDAR between synaptic and extrasynaptic compartments in the dentate gyrus Aim 1a: Determine the levels of synaptic and extrasynaptic NMDAR subunits in control and FASD mice under basal and activated states. Aim 1b: Assess the impact of PAE on mechanisms controlling the localization of NMDAR subunits under basal and activated conditions. Aim 1b1: Determine the associations of NMDA receptor subunits with synaptic scaffolding proteins (PSD-95, PSD-93, and SAP-102) in control and FASD mice. Aim 1b2: Assess the impact of PAE on the levels of phosphorylated and total (phosphorylated + non- phosphorylated) forms of NMDAR subunits in control and FASD mice. Aim 2: NMDAR function is impaired in the dentate gyrus granule cells Aim 2a: Measure whole-cell synaptic NMDAR-dependent currents in hippocampal slices prepared from control and FASD mice following perforant pathway stimulation. Aim 2b: Measure whole-cell NMDA-dependent synaptic and extrasynaptic currents in hippocampal slices prepared from control and FASD mice. PUBLIC HEALTH RELEVANCE: Exposure to alcohol during development has been shown to cause a multitude of dose-dependent effects on the structure and function of the central nervous system. These effects are manifested as a range of physical, behavioral, cognitive and social dysfunctions. The studies proposed in this grant aim to identify neurochemical mechanisms that underlie the damaging effects of prenatal alcohol exposure on cognition, and thus identify novel targets for therapeutic intervention in the treatment of fetal alcohol spectrum disorders (FASD).